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And for your enjoyment... here are some of my old pathology
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Spherocytosis: Spherocytes (look smallish as they don't lie flat, no central pallor) on peripheral smear;
Increased MCHC (hyperchromasia -- remember spherocytosis as the one genuine cause; potassium leaks out of the damaged lipid bilayer and takes water with it)

Acute hemorrhage: Increased reticulocytes (it usually takes about five days for them to appear. You remember
about CFU-E's, erythropoietin and all that; there's generally a thrombocytosis during recovery from a bad bleed)

* Finding increased soluble transferrin receptors is supposed to be
more sensitive and specific for iron deficiency and to avoids some pitfalls
of previous assays, but it remains a research tool update Am. J. Clin. Path. 138: 642, 2012).

B12 deficiency: Low serum B12;
Perform a Schilling test (if you
can get the isotope)

Classic pernicious anemia:
Schilling test becomes normal on addition of extrinsic factor; with the isotope
unavailable, just check the blood for antibodies against
gastric parietal cell antibodies (maybe 70% sensitive and 50% specific if you're just fishing)
and maybe intrinsic factor antibodies
(J. Clin. Path. 62: 439, 2009, even less sensitive and rare if
anti-parietal cell antibodies are not present);
do a good H&P, make a presumptive diagnosis and treat

Anemia affects at least a quarter of the world's population, with a
disproportionate burden among children and non-pregnant women in the
middle- and low-income nations (Lancet 378: 2123, 2011) --
of course the major causes are dietary iron deficiency, dietary folate and B12
deficiency, hookworm, schistosomiasis, and malaria. The loss of productivity
and human potential is terrible.

Even in serious "acute blood loss", where the classic teaching is that
the hematocrit can be normal since red cells and plasma are lost
proportionately, the hemoglobin will probaby be 10 or less by 30 minutes
(J. Trauma 63: 312, 2007).

Hemodilution from excess fluids can occasionally lower hemoglobin and hematocrit in the absence
of anemia. ("Pump him full of normal saline!!")

Remember that hematocrit and hemoglobin will remain normal until plasma volume is restored
(hours to days.)

The bone marrow can increase erythropoiesis to three times normal within a day or so.

Chronic blood loss:

You'll see plenty of people with longstanding bleeding ulcers, GI and GU cancers,
very heavy periods, and so forth on rotations. You'll learn about the special case of
twin-twin transfusion in "Repro".

Many anemias are due, in whole or part, to premature destruction of red blood cells within blood
vessels (INTRAVASCULAR HEMOLYSIS, as in DIC, or when RBC's are sensitized to complement or
mechanically injured or lysed by oxidative stress in G6PD deficiency) or more commonly in the RE system (EXTRAVASCULAR HEMOLYSIS, as when RBC's are too stiff or
fragile or are altered immunologically; in ongoing extravascular hemolysis, expect a biggish spleen). Easy update: Am. Fam. Phys. 69: 2599, 2004.

Falciparum malaria often produces intravascular hemolysis;
the other malarias usually produce extravascular hemolysis.

If the capacity of the ERYTHROID (red-cell producing) bone marrow to produce red cells is exceeded (it
can increase output up to maybe eight times normal), anemia will result.

Regardless of cause, ongoing hemolysis will result in several pathophysiologic changes:

increased total body iron

(the gut knows about the increased erythropoiesis and absorbs more iron -- diminished hepcidin --; if hemolysis is
the only problem, this is seldom serious; look for iron in the Kupffer cells of the liver)

increased reticulocyte count

(this is a measure of the percentage of very young red blood cells; do this FIRST in your workup of
anemia. Savvy labs now do it for you on any patient without a known
cause of the anemia: Am. J. Clin. Path. 124: 129, 2005.

absent serum haptoglobin (mostly if it's intravascular hemolysis but some even if hemolysis is extravascular);
you remember that haptoglobin carries free hemoglobin
and prevents it from being lost via the kidney / oxidized to brown methemoglobin;
we do not believe this lab test is helpful today. If there's ongoing intravascular
hemolysis, hardcore pathologists look for brown
pigment ("renal hemosiderosis")in the proximal tubules -- why?

jaundice (unconjugated bilirubin)and bilirubin gallstones

expansion of the marrow space

(in children, this produces thickened diploe of the skull, with a "crewcut" pattern)

This is a relatively common autosomal dominant hemolytic syndrome (1/5000 people of northern
European stock).

There are several loci, the most familiar being mutated spectrin.

Mutated ankyrin, "band 3", and "protein 4.2" produce the same
effect on the cytoskeleton. Not surprisingly, all are part of the complex
of molecules that gives red cells their shape (Blood 100: 1878, 2002).

* "Big Robbins" is confusing about compound heterozygosity in spherocytosis.
Around 75% of cases are autosomal dominant, the rest mostly autosomal recessive at the
ankryn, spectrin, or 4.2 loci and of course tend to be more severe, often obvious in newborns. They are mostly "compound heterozygotes" since there are a
host of weak-abnormal alleles that seldom match (Semin. Hemat. 41: 118, 2004.)

Anemia is moderately severe, with hemoglobin around 9.

Poor binding of protein 4.1 to spectrin results in a defective erythrocyte cytoskeleton.
This causes loss of the lipid bilayer membrane over the first few days in the bloodstream,
resulting in
spherical RBC's that get destroyed in spleen.

Spherocytes are easy to identify on a smear of peripheral blood because they lack the central pallor
of biconcave RBC's.

In addition, the mean corpuscular hemoglobin (MCHC) is HIGH in this disorder because the spleen
nibbles bits of membrane off the surfaces of RBC's that make it through.

The inadequate cytoskeleton allows the RBC's to rupture easily when placed in mildly hypotonic
solution (increased osmotic fragility). All but the youngest RBC's are destroyed while passing
through the splenic sinusoids.

Treatment is splenectomy, which results in a great subjective benefit and a normal hemoglobin
(though some hemolysis continues.)

Today, you may receive a near-total
splenectomy, leaving behind a remnant, to avoid the untoward effects
(infections, thromboemboli) of total splenectomy (Ann. Surg. 241:
40, 2005.)

In HEREDITARY ELLIPTOCYTOSIS
("hereditary ovalocytosis"), the spectrin (usually) mutation is different (Blood 109: 3538, 2007) , the cells are oval, but
the picture is the same or milder. It's actually more common than spherocytosis and is extremely
common in Malaysia (their mutation, yes, gives resistance to malaria), but is usually
not bad enough to cause anemia.

* Hard-core pathologists / philologists: An elliptocyte has edges nearly parallel;
an ovalocyte is more of a true ellipse.

* Variation on the theme: the rare "hereditary pyropoikilocytosis" is a hemolytic anemia with a
mutant spectrin that won't stick to itself and gets degraded too rapidly. The cells have bizarre
shapes ("like in a burn patient" -- hence the weird name), the anemia is obvious at birth, but the prognosis is good.
The alpha-spectrin allele: Blood 106: 4367, 2005.

HEMOLYTIC DISEASE DUE TO ERYTHROCYTE ENZYME DEFECTS

Inherited disorders of enzymes in the hexose monophosphate shunt (glutathione
synthetase, G6PD), other glutathione pathways, or glycolytic (hexokinase, pyruvate kinase) enzyme systems in
erythrocytes result in oxidative damage to RBC's.

Deficiencies of each enzyme may be mild or severe, the thus the clinical pictures are widely
variable.

This was a serious problem for black servicemen taking antimalarials in Vietnam. Sulfas,
nitrofurantoin, and even aspirin can be hazardous for these people, depending on how badly deficient
they are.

Some folks with G6PD get massive acute hemolysis from fava beans; some do not.
We don't know why -- it doesn't seem to be particular alleles, and as affected
children grow up they often lose the trait (Int. J. Heme. 83: 139, 2006).
Part of the problem is that we can't test prospectively by passing out fava beans to
test subjects and seeing whether they get life-threatening hemolysis. Stay tuned -- I believe
there is a second metabolic defect.

Following exposure to the offending oxidizer, the older red cells are hemolyzed.
The exposure can then usually continue without the patient remaining super-sick, as the
vulnerable red cells are gone. Be sure you understand this. Since hemolysis in G6PD
deficiency is intermittent, the big spleen and gallstones seen in other hemolytic diseases usually don't develop.

If the patient also has Gilbert's, severe neonatal jaundice results
(Proc. Nat. Acad. Sci. 94: 12128, 1997). The combination can also
occur later in childhood (Ped. Hem. Onc. 22: 561, 2005), or G6PD deficiency
without Gilbert's
can cause severe jaundice, with or without anemia, in babies.

Deficiency of PYRUVATE KINASE (for anaerobic glycolysis) is a very common Amish autosomal
recessive birth defect. (Patients are mostly of northern European ancestry.) There are other mutations as
well. Some molecular biology: Blood 82: 1652, 1993; Blood 89: 1793, 1997.

There is not enough energy to run the RBC membrane sodium pump, so the cells eventually
undergo osmotic lysis.

Because these people have so much 2,3-DPG in their erythrocytes, they tolerate their anemia very
well.

Sickle cell substitution of valine for glutamine at the sixth position of the β chain (βS). Two
α chains plus two βS chains makes HgbS.

Eight percent of blacks in the US are carriers, and 1 child in 600 is affected. There are around 100,000 sickle
cell patients in the US.

There's also sickle-cell disease among Sicilian whites; for some
reason it averages milder than in Africa (Arch. Ped. Adol. Med. 150: 170, 1996).
And there are some affected areas in East Asia.

In Britain and elsewhere, there has proved to be little demand for
screening among pregnancies in populations at risk; people are now talking about being
far more aggressive about reaching these people (BMJ 341: c5132, 2010).

Sickling of a cell is reversible until the tactoids wreck the cell membrane ("how" involves spectrin
tetramers dissociating and re-associating: Blood 81: 522, 1993). Then it's irreversible and the cell
eventually gets lysed. Red cell life span averages about twenty days.

Dehydration increases MCHC and promotes sickling.

Hgb F effectively prevents sickling, so patients don't sickle until they are around two years old and
no longer have much Hgb F. Some genotypes at other loci keep a lot of Hgb F around
through life, and this makes SS disease far milder (Blood 118: 19, 2011).

Hgb A inhibits sickling, so heterozygotes (Hgb AS) do not have much trouble with sickling at usual
oxygen tensions.

Hgb C does not inhibit sickling so well as Hgb A. Hgb SC mixed heterozygotes do sickle, though it
is not so severe as Hgb SS homozygotes, and the spleen is typically lost later in childhood (Blood
85: 2238, 1995).

When oxygen tensions are low, sickled cells tend to stick tight to one another. This doesn't help
things. Nobody really understands why this happens; some people think the sickled cells grow tiny
spikes and stick together like burrs / velcro (described classically in Blood 81: 3138, 1993). Somehow
the cells also get a lot stickier to endothelium, probably accounting for a lot
of the strokes and other occlusive phenomena.

*
Children who have had a stroke
and are regularly transfused with healthy red cells to prevent
more continue to have strokes despite treatment (Blood 117: 772, 2011). Your lecturer
believes this is due mostly to the stickiness of SS red cells.

As the red cells lose oxygen / go to areas with lower pH, they tend to sickle.
This isn't a problem in most areas.
However, flow of blood through the spleen and marrow tends to be slow.
Sludging of cells in the spleen first enlarges it (early childhood) then
red-infarcts it by age 6 ("autosplenectomy"). The major problem then is
vulnerability to pneumococcal and H. flu ("encapsulated organisms")infections. This fact also explains the marrow necrosis that
underlies some of the crises in sickle cell disease.

"Chest syndrome", with fever, chest pain, a lung infiltrate, and leukocytosis, is
still not altogether understood
()NEJM 342: 1855, 2000; morphine as a cause Clin. Pharm. Ther. 75: 140, 2004).
Occlusion of the vasculature is probably the key, especially
embolization
from infarcted marrow; it also often runs with a chest infection.
It's pretty much impossible to tell it from pneumococcal pneumonia or pulmonary infarct,
and it's treated as if it were pneumonia; it remain the leading cause of death
in sicklers. Controlling costs (~$30,000 per admission) by a protocol:
Pediatrics 127: e480, 2011.

* Anatomic pathology of pulmonary hypertension in sickle cell disease: Hum. Path. 33:
1037, 2002. It looks to me like some of this is from microembolizatoin.
Today, depletion of nitric oxide from the blood by
the hemoglobin released by intravascular hemolysis is blamed for much of the
pulmonary and other complications of sickle cell disease: Blood 116:
687, 2010.

* Survival is improving; the chance of a child with sickle cell disease dying is a bit less than 1% per year
(Blood 103: 402, 2004); the rate of stroke is about the same.

These people often become addicted to opiates, and come to be despised by health-care providers as
"drug seekers" or worse. Stigmatization of sicklers is unfair and
scandalous (BMJ 318: 1585, 1999).
They present the same kind of pain management problems as do cancer
patients, only it is worse, since they live longer. Physicians are just now starting to get wise to this (Ped. Clin. N.A.
47: 699, 2000);
managing it appropriately seems to reduce hospitalization by about half (Ann. Int. Med. 116: 364,
1992; epidural fentanyl is eminently sensible Pediatrics 93: 310, 1994).

About half of sicklers survive to age forty. Other genes modify the severity of the disease, and are
the major influence on survival (NEJM 330: 1639, 1994.

As you recall, heterozygotes are relatively protected against falciparum malaria, which
is of course
why hemoglobin S is so common in Africa (reconfirmed JAMA 297:
2220, 2007; mechanism is at least in part enhanced phagocytosis of ring-parasitized
red cells with sickle or thal Blood 104: 3362, 2004). However, the protection is by no means absolute,
and malaria remains a major killer of children with sickle-cell disease in Africa: Arch. Dis. Child. 89:
572, 2004.

"Big Robbins" could have mentioned that sickle cell trait tends to destroy the
renal medulla by the end of the teenaged years. The military discovered during the Vietnam era that sickle carriers tended to die suddenly during
the roughest parts of basic training or when they became stressed
in the heat; today the military just
makes an extra effort to keep these people well-hydrated which seems to solve
the problems. Sports participation (especially college football) for these kids
was the subject of a series of lawsuits in the past few decades; in April 2010,
the NCAA (as part of the settlement of the Dale Lloyd case) agreed to mandate that all college athletes be screened for sickle cell and
those testing positive be given informed consent and kept well-hydrated.

You will learn cost-effective screening procedures for sickle cell disease and trait later in your
career.

Screening newborns for sickle cell disease allows early administration of pneumococcal vaccine, a
potentially life-saving intervention. For black newborns, the extra cost is only $3100 more per life
saved than not screening (J. Ped. 118: 546, 1991).

* We wisely screen all newborns. There's a fallacy in the above
article ("$450 billion per life saved screening low-prevalence non-black populations" -- anybody
can check the wrong box, and there's no shortage of Sicilians and Chinese ancestries.)

Nonablative marrow transplant from HLA-matched siblings is now giving what seem to be excellent
results, with patients free of both the disease and graft-versus-host: JAMA 312: 48, 2014.
I'm in agreement with the NIH team that thinks both children and adults deserve this curative
therapy (Blood 118: 1197, 2011.) Adults may benefit from non-myeloablative therapy -- they become
chimeras for normal red cells.

More about treating the hemoglobinopathies:

Cord-blood allografts from HLA-identical newborn sibs
followed by administration of growth factors
have cured sickle cell disease (J. Ped. 128: 241, 1997).
It is now routine when there is a matched sibling
(Lancet 360: 629, 2002).

Hydroxyurea / hydroxycarbamide (Blood 79: 2555, 1992; Medicine 75: 300,
1996; Blood 115: 5300, 2010, a ribonucleotide reductase inhibitor)
enhances the fetal hemoglobin response (nobody knows how) and diminishes the
ability of red cells to sickle. Physicians have been reluctant to prescribe it
long-term but the Greeks have found that it seems to improve length and quality
of life into adulthood (Blood 115: 2354, 2010). The effect can be augmented nicely by erythropoietin (NEJM 328: 73,
1993).

* Watch for inhibitors of the gardos channel, which modules
entry of water into the cell; these might well prevent sickling itself.
The inhibitor is ICA-17043 (HemeOnc Clin. N.A. 19: 975, 2005). Study still underway.

* In the early 1990's, Illinois's 1183 sickle cell patients had a median
of 3 hospital admissions yearly and consumed $59,000,000 in two years,
or about $30,000 per patient per year; national numbers
are similar (Pub. Health. Rep. 112:
38 & 44, 1997; they talk about strategies to improve out-of-hospital compliance,
doctors' efficiency).

Sickle cell disease is undertreated. After reviewing JAMA 312: 1033, 2014 (standards for treating sickle cell)
I was puzzled, as the authors seem to have been, about why most / all sicklers aren't on
hydroxyurea and getting frequent transfusions.

Disorders with decreased synthesis of a structurally normal globin chain.

The other chain is made in normal quantities. Aggregates of this chain accumulate in the
normoblasts and cause intramedullary hemolysis. (Beta chains are worse than α chains in this
respect.)

* Aggregates of alpha chains may be recognized as "Fessas bodies".
They are responsible for the intramedullary destruction of normoblasts in the beta-thalassemias.

I will resist the temptation to talk about the molecular genetics of the thalassemias except in the most
basic terms. Those seeking an appreciation of the range of defects may begin with
Mayo Clin. Proc. 76: 285, 2001; Clin. Chem. 46: 1284, 2000.

ALPHA-THALASSEMIA: Asian and African genes. Usually the genes are deleted.

There are two genes for the α chain per chromosome, or four genes total. In the various α
thalassemias, one or more are hurt.

One gene hurt ("silent carrier"): No health problem; red cells may be on the small side;
maybe 3% Hgb Bart's
(four γ chains) at birth, no
Hgb H (four β chains) as adult.

Two genes hurt ("α thalassemia minor" or "trait"): Red blood cells tend to be small (MCV 82 or
so) but anemia is unusual; 5-10% Hgb Bart's at birth, trace of Hgb H as adult. Seldom noticed.

This is a little bit subtle. The genotype α α/ - -
(mostly Southeast Asian) is worse than the genotype α -/α -. Why?
HINT: Which is more likely to be the parent of a child who will die in the womb?

We have classically screened for alpha thal trait by looking for Hgb H ("Bart's carriers").
A new method, which is under study, looks for the obscure "zeta globin",
elevated in these folks (Am. J. Clin. Path. 129: 309, 2008).

Three genes hurt ("Hgb H disease"): Hemolytic anemia throughout life; 25% Hgb Bart's at birth;
25% Hgb H as adult. Hgb H is unstable and these patients have mostly a "bite cell" anemia, Heinz
bodies and hemolysis. It also have excessive affinity for oxygen, and does not give
it up easily enough for optimal tissue function, so the tissue hypoxia is worse than
you'd expect for the degree of anemia. It's fairly well-tolerated,
depending on exactly what mutations are present (NEJM 364: 710, 2011).

Four genes hurt ("hydrops fetalis"): Fetus dies in third trimester
as it has only Hgb Bart's, which has an excessive
oxygen affinity and also has lysis of normoblasts in the marrow due to
four-gamma tetramers. (A novel hemoglobin with two zeta chains and two gamma chains
in the early fetus allows
survival for a while.) Death is due to congestive heart failure due to anemia and ineffective
oxygen delivery to the tissues, so the fetus dies extremely
edematous. (The other common causes of such a severe anemia
are parvo 19 and Rh incompatibility.)

* The crew at Brown, your lecturer's alma mater, brings a fetus with Bart's hydrops to term and are
going to bone-marrow-transplant.... (Ob. Gyn. 85: 876, 1995). Your lecturer sees this as a prime
example of the "law of inverse care"; you may disagree.

NOTE: It's desirable for a person with sickle cell disease or trait to have deletions of an α gene
or two (why?) See J. Clin. Invest. 88: 1963, 1991.

BETA-THALASSEMIA: Mediterranean genes, mostly

There is one gene for the β chain per chromosome, or two genes total. In the various beta
thalassemias, there is a problem with the mRNA and enough β chains do not get produced.

Heterozygotes ("beta thalassemia minor" or "trait"): mild or no anemia; hypochromia and
microcytosis are usual, but target cells, teardrops and basophilic stippling are seen only
in a minority of cases (Am. J. Clin. Path. 129: 466, 2008). You
may not be able to appreciate either the hypochromia or the microcytosis on smear, because the cells
tend to assume a pancake shape, without central pallor. Hgb F is sometimes increased;
Hgb A2 is usually increased (because these have no beta chains, of course -- and this is the ONE
time you might actually pick up "delta thalassemia", a lab curiosity with
problems making
delta chains, since your "beta thal trait" non-patient lacks the usual increase
in Hgb A2.) It's VERY important to pick up your beta-thal-minor patients
for genetic counselling and so that somebody else doesn't treat them for "iron deficiency anemia".

Homozygotes ("beta thalassemia major"): severe anemia beginning in infancy as the baby switches
from Hgb F production. Patients have the stigmata of chronic hemolysis ("crewcut" skull x-ray,
etc.), and little or no Hgb A, with extra Hgb F
(usually most of the hemoglobin in Hgb F) and sometimes extra Hgb A2. As they must be transfused repeatedly
and over-absorb iron due to ineffective erythropoiesis suppressing hepcidin, they have classically died of iron overload in their teens. The iron
chelators (deferiprone, desferrioxamine, deferasirox -- the new one, Blood 116: 537, 2010 --
others) have been a great help, and now these
people will probably live out a normal lifespan of good quality.
The current major problems with the chelators (especially
deferiprone) have been joint damage,
agranulocytosis and zinc deficiency;
(no surprise): Blood 80: 593, 1992; NEJM 332: 918 & 953, 1995; Br. Heart. J. 73: 486,
1995; Blood 90: 994, 1997. Marrow transplant: Arch. Dis. Child. 66: 517, 1991.
Improved long-term results without bone marrow transplant: Blood 104: 34, 2004.

Every once in a while, one or more globin genes can be lost in the myelodysplastic
syndrome, producing an acquired thalassemia (Blood 103: 1518, 2004).

* Mainland China's pathologists develop and begin implementing "preventive
genetics" to eliminate the devastating thalassemias: J. Clin. Path. 57: 517, 2004.
This isn't the place to talk about the "ethical" and "human rights" implications;
the mere fact that we in the United States CAN do so is a real privilege.

* Heads-up: Ignore "fine basophilic stippling." It is usually an artifact
caused by slow-drying of a smear.

You'll frequently need to distinguish the two great microcytic anemias: thalassemia and iron
deficiency. In the US, they're about equally common; remember that there are
a great variety of genetic thal-minor variants
(Am. J. Clin. Path. 127: 192, 2007).
A variety of formulas exist to give you the first guess. All are based on the fact that
thalassemia cells tend to be smaller with a higher hemoglobin concentration, and iron-deficient
cells tend to be larger with a lower hemoglobin concentration (Arch. Path. Lab. Med. 116: 84,
1992).

The formulas don't factor hemoglobin E (which one might consider
a thal variant since the mutated beta-chain is sometimes undersynthesized) into the picture, since they were developed before our
country was enriched by the Southeast Asian immigration. Easy to remember: Mild microcytic
anemia with near-normal RBC count: Thal minor or hemoglobin E.

The mechanism has been worked out, mostly, and is complicated. There is some sort of immune
attack on the marrow, and cells evade the attack
by mutating the
gene (PIG-A) that makes an
inositol-based anchor for a group of surface proteins, including CD59 that confers resistance to lysis
by the body's own complement
(NEJM 330: 249, 1994; J. Clin. Invest. 96: 201, 1995; Blood 85:
1640, 1995).

This disease also affects myeloid cells and megakaryocytes, proving it's a stem cell problem. (In
addition, it sometimes turns into marrow failure, i.e., it's a
Nowell's law hit. Or PNH may supervene
when the immune attack on the marrow has already been
underway as a known "aplastic anemia." How this happens:
Ann. Int. Med. 136: 534, 2002.

Additional problems include the generalized toxic effect of a lot of
hemoglobin floating free in the blood (soaks up nitric oxide that you
need to keep the right vessels open), loss of iron into the urine (eventually producing iron deficiency)
and
thromboses especially in liver and brain veins (once attributed to abnormal platelets, it's
more likely due to abnormal complement activation).
Like all hemolytic processes, it can render
people folic acid deficient.

Managing PNH is mostly about treating the symptoms, and
hope it remits (i.e., your internal milieu changes somehow and there's selection against the bad
clone, which is fairly common: NEJM 333: 1253, 1995).
Treatment with the antibody eculizumab, which blocks the activation of
C5 to C5a and the formation
of membrane attack complex, is the breakthrough
for PNH (NEJM 355: 1233, 2006; update Blood 111: 1840, 2008;
Lancet 373: 759, 2009); this controls hemolysis and -- surprisingly, maybe -- thrombosis.

* Eculizumab's dreaded side-effect
is greatly-increased vulnerability to meningococcal sepsis.
Immunization and penicillin / erythromycin must be given these patients.
It is also extremely pricey and doesn't seem to prolong life.

Extravascular hemolysis resulting from sensitization of RBC's to the patient's own IgG (sometimes
IgA). Portions of the membrane are removed bit by bit ("partial phagocytosis"), eventually
imparting the spherocyte shape.

Since red cells have no class I HLA antigens, T-cells
do not attack them.

IMMUNE COMPLEX MECHANISM (quinine-quinidine type): drug-antibody complexes get absorbed to
innocent bystander RBC's, which are then lysed by complement. Phenacetin and cephalosporin are
also frequently implicated in this type of hemolysis.

AUTOANTIBODY MECHANISM ("Aldomet" type): the drug somehow causes one to make antibodies
against one's own Rh antigens (everybody has some Rh antigens, even though Rh negative).

Chronic cold agglutinin disease is fairly common in lymphoma, or may be idiopathic. (These people
should dress warmly.) Curiously, hemolysis occurs in the liver, not the spleen, in these patients.

* The presence of cold agglutinins is a major nuisance for blood bankers trying to type blood.
Let us worry about it.

COLD HEMOLYSIN AUTOIMMUNE HEMOLYTIC ANEMIA

The usual disease is PAROXYSMAL COLD HEMOGLOBINURIA and the auto-antibody is * Donath-Landsteiner
auto-antibody, a polyclonal IgG against P blood-group antigen on the RBC's.

The classic story is the patient goes skiing and falls in the snow; the next time, after rewarming
(complement works when it's warmer),
the patient voids, the urine is dark
brown.

Once a famous sign of syphilis,
paroxysmal cold hemoglobinuria now it most often follows the flu or
arises mysteriously. It's actually quite common in children now that we've started
looking for it (in fact, it's the most common autoimmune hemolytic anemia), and it's
occasionally a genuine side-effect of immunization.

These hemolytic anemias seldom last long, but indicate serious disease.

* "March hemoglobinuria" is another cause of intravascular hemolysis from trauma; it is well
tolerated.
"Burr cells", with little projections, are supposedly seen in patients with uremia
(i.e., symptomatic kidney failure.)

This is a broad term for all problems in which the normoblasts (and, often, the other cells in the
body) cannot synthesize DNA fast enough to keep up with the growth of their cytoplasm.
("Nuclear-cytoplasmic asynchrony". This is easily the most plausible explanation; remember you
also need B12 to do methionine and methyl-malonic acid). Although patients will be anemic, the
baby cells (-"blast") end up big ("megalo-"), and a good pathologist can immediately recognize a
"megaloblastic marrow smear" by the big, blue cells with lots of cytoplasm and immature-looking
nuclei. (Polys and their precursors are big, too. You'll see pictures; I won't ask you to make the
distinction on an exam.)

Regardless of the cause, expect to see:

anemia (and maybe neutropenia and maybe thrombocytopenia)

increased mean corpuscular volume (why?) with normochromia and considerable anisocytosis (ask
a pathologist to show you a "macro-ovalocyte"; other cells lines are also affected, producing
giant metamyelocytes and giant bands)

hyper-segmentation of the neutrophil and eosinophil nuclei (why?)

shortened red cell survival time (often, much of the hemolysis takes place in the marrow; the marrow
may appear hypercellular and serum LDH-1 levels, suggestive of hemolysis, can be extremely high)

Rule: Count one hundred neutrophils. Separate segments are defined to be masses separated by a
thread composed entirely of heterochromatin. If you see one neutrophil with six segments, or five
with five segments, you have established the diagnosis of megaloblastic anemia. I
am suspicious when I see a three-lobed eosinophil does
it, too.

This is extremely common, especially
in older folks; one group argues that there must be 800,000
undiagnosed cases (Arch. Int. Med. 156: 1097, 1996).
Once dreaded and very lethal ("pernicious"), the available of injectable B12 (in the old days, a pound
of raw liver per day by mouth, or liver injections) has now rendered this common problem almost
innocuous.

The basic problems is chronic atrophic gastritis with destruction of the parietal cells and
failure of intrinsic factor production.

Often (maybe 40% of the time) there is some antibody that sticks to intrinsic factor as well,
preventing its binding to B12 ("blocking antibody"). There's also likely to be antibodies
against receptors in the ileum where the complex must be absorbed ("binding antibody").
Assay J. Clin. Path. 46: 45, 1993 (* contrary to older sources, either can be present without the
other).

* The antibodies in "pernicious anemia":

Type I: Block the binding of B12 and intrinsic factor;

Type II: Block the binding of the B12-intrinsic factor complex to its cubilin receptor in the ileum

Type III: Antibodie against parietal cell canaliculi

* While we are ordering unnecessary lab tests, most of these patients have elevated serum gastrin
levels, too (why?).
Despite the fact that we can test the antibodies, the main problem seems to be T-cells that destroy
the gastric mucosa, with the antibodies being an epiphenomenon.

On rotations, be aware that it now seems that
in pernicious anemia, the serum B12
level may be normal. Check the serum methylmalonic acid and homocysteine levels
if you have reason to suspect B12 and/or folic acid deficiency; they are likely to be up
and some say this is a good screen.

The elevated homocysteine may be a risk factor
for atherosclerosis and/or deep vein thrombi.

In addition to the problem making good blood cells, B12 deficiency (from whatever cause) is noxious
to the brain and cord, probably because of increased levels of methyl-malonic acid and propionic acid.
Demyelinization of the posterior columns of the spinal cord happens early and causes loss of
proprioception and some paresthesias, as in tabes dorsalis. Eventually, dementia occurs. These
problems may precede the anemia (Postgrad. Med. 91: 231, 1992; Postgrad. Med. 88: 147, 1990).

In the 1980's, I had the rare privilege of autopsying a "virgin" pernicious anemia patient, a
gentleman who was institutionalized for five years with "Alzheimer's disease". His physicians drew
blood from time to time, but never noticed the anemia, the MCV of 140, or the hypersegmented
neutrophils reported by the lab. Bad care. I noted each of the following "classic" changes:

findings of anemia (pallor of all organs, big heart)

slight icterus (red-cell precursors are also being destroyed, hence
the high LDH seen in megaloblastic anemias -- ever hear of the "lemon yellow" pernicious anemia patient?)

NOTE: Often the lateral columns are affected, too, though less dramatically. This is called "subacute combined degeneration
of the cord", typical of B12 deficiency.

To make the diagnosis, we used to perform the two-part
SCHILLING TEST.

Give the patient an injection of normal B12 first (why?)

Then administer radioactive B12 by mouth. A healthy person will excrete the radioactivity in the
urine. If your patient, for any reason, cannot absorb B12 via the gut, the urine will not be
radioactive.

If your patient cannot absorb B12 via the gut, then give him or her a dose of radioactive B12
with
intrinsic factor. If this causes the radioactivity to appear in the urine, you know the patient lacks
intrinsic factor. If the radioactivity still fails to appear, you know there's some problem with
absorption (i.e., one of those antibodies and/or some disease of the gut).

Okay. Alas, the long-time supplier of the isotope withdrew it
from the market in 2001. Stay tuned. Nowadays, you'll probably confirm your clinical
impression of addisonian pernicious anemia by ordering a serum anti-parietal cell
antibody; maybe
70% of them are positive.

It's common knowledge that patients with autoimmune gastritis, whether or not they have pernicious
anemia, are at substantial risk for gastric cancer (carcinoma, carcinoid; old papers Cancer 71:
745, 1993 and Arch. Path. Lab. Med. 113: 399, 1989). It's ironic that, while the Japanese
endoscope almost everybody (and often finding the highly-curable early gastric cancer lesions),
we're just now getting used to the idea of endoscoping pernicious anemia patients regularly. For
some better-late-than-never common-sense see Gut 34: 28, 1993; endoscopy every five years, more
often if dysplasia is found, seems reasonable (Gut 31: 1105, 1990;
policy-makers take notice). There's been no resolution, and this seems weird in a time when
"everybody" after a certain gets colonoscopies.

Classic "addisonian" pernicious anemia is primarily a disease of people of northern European
ancestry, though any race can be affected. The sex ratio is about equal, which is unusual for an
autoimmune disease.

"Juvenile pernicious anemia" mimics the adult disease in its hematologic and nervous system
manifestations. These patients don't usually have autoimmunity, but instead are born without good
intrinsic factor, or without receptors for the complex. Tip: Check the urine for methyl-malonic acid
(why?)

OTHER CAUSES OF B12 DEFICIENCY

"Inadequate diet" today means vegetarianism, especially
if extreme. "Vegans", who will take no food of animal origin,
all get B12 deficiency in a few months unless they supplement.
B12 deficiency is rampant among today's "amateur" vegans, many of whom are
teens (Am. J. Clin. Nutr. 76: 100, 2002).

As a physician, you need to be aware of the very serious dangers
of food faddism, especially vegetarians who do not know EXACTLY what they
are doing.

Today, many people report feeling better
taking only limited amounts of animal products.
This probably includes the 7% of entering Year I medical students
who self-identify as vegetarians (J. Am. Diet. Assoc. 107: 72, 2007) --
many are religious/cultural;
these people are seldom militants and not surprisingly, maybe half have given up
vegetarianism
by the time of graduation.

By contrast, cult-vegetarians, the ones most likely to get into
trouble, are hard to deal with.
("I can't take that particular medication because I read that the
gel-capsule is made from animals.")
The one's I've known grandstand ("Meat is murder!"), choose to
believe even the most obvious pseudoscience, and
are hostile to real evidence-based medicine.
The greatest danger is to their children, and this is now a major
public health problem.
More about this under Nutritional Disease.

If your whole stomach is gone after some big operation, you'll need B12 supplementation, of course.
But this isn't true pernicious anemia.

Worth knowing -- if the salivary glands are lost, B12 deficiency results due to lack of
salivary-produced * haptocorrin, which protects B12 in the stomach. If pancreatic
insufficiency is present, proteases may not be sufficient to split the * haptocorrin from the B12
to allow it to complex with intrinsic factor.

* Trivia: The receptor that absorbs intrinsic factor in the ileum is called "cubilin".

If you have malabsorption (sprue, Whipple's, lymphoma, scleroderma, others), or if you have the
fish tapeworm on board, or if you have a blind loop (post-surgery, duodenal diverticula) full of
bacteria, or if your ileum is messed up badly by Crohn's disease, you may need B12.

There's a good serum assay for B12. It's expensive, but perhaps an occasional
screen is worthwhile, more for the mental problems that the deficiency causes
especially in the elderly. I'd prefer you start your anemia workup with a
reticulocyte count first.

* Hey Doc! Want to keep your poorly-educated patients happy and coming back ($$)? Some
physicians diagnose "pernicious anemia" wantonly, and prescribe monthly B12 shots, which are red
(ooh, pretty), painless, inexpensive, and harmless. Further, once you start doing this,
it'll be hard to prove the patient didn't originally need the treatment and doesn't
need to continue. However happy this common practice may make
people, I have a ninth commandment problem with it. I hope YOU do, too.

This is disturbingly common in the U.S., and not just in the alcoholics, oldsters, and babies cited in
"Big Robbins". Contrary to your text, the deficiency need not be "gross". You need some
vegetables in your diet every once in a while, and many Americans don't like them. (In the poor
nations, many people can't afford them.) If you lack folic acid, you can't shuttle your one-carbon
units (i.e., methyl and formyl groups) around.

In pregnancy, the fetus leeches out Mom's folic acid, which may already be in short supply.
Likewise, in hemolytic disease and in carcinomatosis, folic acid supplies often drop, a "relative folic
acid deficiency" is unmasked, and a superimposed megaloblastic state develops.

Phenytoin and the birth control pill are infamous for interfering with the absorption of folic acid. Of
course, so can other malabsorption problems (sprue and even GI lymphoma can present this way). Hemodialysis takes the vitamin out of the body, too.

A blood assay for folic acid is available. Again, it's expensive. I'd prefer you not order these for all
your microcytic anemia patients at the onset of your workup. Tip: You can also detect folate
deficiency by assaying the urine for formimino-glutamic acid (FIGlu), a breakdown product of
histidine that requires folate for further processing.

BEWARE. Supplementing a patient with pernicious anemia with big doses of folic acid will
improve the hematologic picture (nobody knows why) and exacerbate the brain disease (nobody
knows why). This is the main reason that only small amounts of folic acid are put in over-the-counter not-for-pregnancy
vitamins.

B-12 AND FOLATE UNRESPONSIVE MEGALOBLASTIC ANEMIA

Obviously, anti-DNA chemotherapy will produce megaloblastic changes.

* Anemias induced by chemotherapy tend to be undertreated, probably
because they are difficult to treat.
Perhaps the new, more-effective erythropoietin-like drug darbepoietin will
prove helpful (Cancer 95: 613, 2002).

Occasional megaloblastic anemias respond well to vitamin B1 (thiamine) or vitamin B6
(pyridoxine).
These are usually acquired, and probably reflect Nowell's law hits (i.e., there is an increased
leukemia risk.)

The "average diet" contains 15-20 mg of iron daily, mostly as heme in animal products
which is readily absorbed. This is plenty for a majority of people. However, many folks (growing
children, women with heavy monthly blood loss or pregnancy, those losing blood from disease)
need more than this, and plenty of people are on iron-poor diets ("I'm a vegetarian and I don't believe in pills!",
poverty, and/or ignorance.)

You already know that iron is absorbed (in limited, regulated quantities) in the duodenum, shuttled
around on transferrin, used in hemoglobin, myoglobin, and cytochromes, and the storage supply
found to ferritin as the invisible short-term form ferritin and the copper-penny, Prussian-blue-stainable long-term form
hemosiderin.

If you look in the marrow, you'll find zero stainable iron, and probably
more than the usual number of red blood cell precursors though they're quite small.
Rumor
has it that they are more numerous because they take longer to develop and
perhaps divide a few more times, accounting for the hyperplasia.

A person may become iron-deficient by:

heavy menstrual loss (Shakespeare's Juliet had "green-sickness", iron deficiency signs attributed to
being in love for the first time)

bad diet (there's not much iron in twinkies, fries, or diet pepsi;
half of adults in the poor nations are iron deficient).

Heme iron is much better absorbed
than iron from beans and so forth. Especially, there is disappointingly little usable iron in
spinach; what's there is oxalate-bound and unavailable.

Poor diet is seldom the sole cause in U.S. adults consuming an adequate
number of greaseburgers weekly.
However U.S. kids can and do
become iron deficient, despite "Big Robbins". There is very little iron in
breast milk, and children do become deficiency as a result. No one knows the "best"
amounts and timing for supplementation (Ped. Clin. N.A. 48: 401, 2001).
Perhaps one US baby in 11 is iron-deficient enough to be anemic from it
(J. Ped. 154: 44, 2009).

Iron deficiency is one of the great hazards of pregnant women. Improving the iron status
by oral supplementation goes a LONG way to improving neonatal health and even avoiding
low-birth-weight (BMJ 346: f3443, 2014).

Despite a great deal of disinformation by the vegetarian community leadership,
who cherry-pick obscure journals,
it is a plain fact that it is difficult for vegetarians
to get adequate absorbable iron in their diet. See, for example,
Am. J. Clin. Nutr. 89: 1685-S, 2009 (soybeans / tofu are low in iron,
but iron in pills made from soybean ferritin is as bioavailable as ferrous sulfate
and vegetarians might accept it more readily.) Europe's adult vegetarians tend to be both
iron and B-12 deficient, with corresponding abnormal labs (Eur. J. Haem. 69:
275, 2002). England's young vegetarians are
much more likely to be iron-deficient than their omnivore peers (Pub. Health. Nutr. 6: 485, 2003).
Even the midwives are delivering
serious warnings to pregnant vegetarian women about multiple deficiencies, including
iron (J. Midwifery Women's Health 53: 37, 2008). Competitive athletes, who are reality-oriented,
know they need to take supplemental iron if they're vegetarians (Nutrition 20: 696, 2008).

Anemia of vegetarianism is likely to have normal indices, since patients are both
iron deficiency and B-12 / folate deficient. An American vegetarian mother who does exclusive
breast-feeding for the first sixteen months almost kills her child: Ped. Heme. Onc. 29:
74, 2007.

Not everyone can absorb oral iron well. People with celiac sprue, atrophic gastritis, and even
bad helicobacter infections may not absorb oral iron well enough for it to be an effective treatment.

malabsorption (sprue, those others)

no HCl and/or no access of food to the duodenum (as after ulcer surgery)

Doc: If you find iron deficiency, you MUST find the cause. It is cancer of the GI or GU system
until proven otherwise.

Around 10% each of toddlers, teenaged girls, and moms are iron deficient,
and of these, around half are anemic (JAMA 277: 973, 1997).
Newer numbers: Almost 20% of kids are iron-deficient, with 5% anemic (Clin. Ped. 44:
333, 2005); easy to diagnose, but these kids are still not being followed up.
Of
course this is deplorable. An attempt by the English to alter the
junk-food habits of their underclass through "education"
was an expensive, complete failure (Arch. Dis. Child. 76: 144,
1997). Older folks with congestive heart failure and mild iron deficiency (even without anemia)
do MUCH better when you pick it up and address it (Heart 100: 1414, 2014.)

Regardless of the cause, the iron-deficient patient eventually develops a hypochromic, microcytic (why?)
anemia, which can be very severe.

You'll be impressed the first time you see tiny red cells with broad central pallor (more than the usual 1/3).

For some reason, elongated "pencil RBC's" are common in iron deficiency (no one knows why, but
they are quite distinctive for true iron deficiency: Am. J. Clin. Path. 129:
466, 2008), and the platelet count
tends to rise (also mysterious).

Textbooks describe a variety of additional physical findings that are supposed to be more or less
specific for iron deficiency. This includes koilonychia (spoon-shaped nails), beefy "atrophic" glossitis (supposedly),
intestinal malabsorption, and upper esophageal webs ("Plummer-Vinson"; the link to iron deficiency
is almost certainly a myth, and I have my doubts about the others, since they make no sense
physiologically).

Here, there's plenty of iron in the body, but it isn't available to the normoblasts, but stays in the big
fixed macrophage in the center of the erythroid island.

This unfortunate effect is mediated by increased body levels of interleukin 1 (* and probably other
cytokines too), i.e., the macrophages are phagocytosing somewhere in the body, and the "acute phase
reaction" has been going on long enough to cause lowering of the hematocrit.

The recently-discovered hormone hepcidin is now the central
player (J. Clin. Inv. 113: 1251, 2004; Blood 111: 2392, 2008);
angry macrophages make it themselves, and cytokines (notably IL-6) inflammation elsewhere increase its production by the liver.
Hepcidin is usually way up in the blood in anemia of chronic disease if you're able to measure it.
Extra hepcidin binds to, and interferes with, ferroportin on the iron-storing marrow macrophages so they do not release their iron
so readily. Stay tuned.
This is a common, often-overlooked / undertreated problem in AIDS (J. Inf. Dis. 185(S2): S-105 & S-110, 2002);
perhaps the availability of newer erythropoietin-like medications will result in this being
treated more effectively.

Patients have a hypochromic-microcytic (if severe enough -- why?) anemia with a hemoglobin of around 8-10 gm/dL.
Bone marrow iron stores are increased.

In the U.S., the usual causes are rheumatoid arthritis, osteomyelitis, TB, and huge bedsores.
(Remember these also cause amyloidosis A; same underlying problem.) Treat the underlying cause,
Doc.

* If you want to diagnose and monitor the disease, try serial zinc protoporphyrins (Blood 81: 1200,
1993; why does it work?)

Artificial erythropoietin came into use for anemia of chronic disease during
the late 1990's, and is now common.

SIDEROBLASTIC ANEMIA

Once again, there's plenty of iron in the body, and this time, it's even in the normoblasts. But in this
relatively uncommon problem, patients have difficulty placing the iron into their heme rings.
Instead, it remains in the mitochondria, which light up as Prussian-blue positive chunks in their
ordinary position around the normoblast nucleus (hence the cute term "ringed sideroblasts").

Commonly, only some of the red cell precursors are affected (i.e., Nowell's law has been operating;
this is a fairly common finding in the early
myelodysplastic syndromes: update Blood 106: 247, 2005.) Alcoholism and isoniazid therapy also
get cited.

Some other cases of sideroblastic anemia respond to big doses of pyridoxine, and
in these
cases, the pyridoxine binding site on the protein is what was hit by the mutation (of course).
More on this: Blood 93: 1757, 1999.

PURE RED CELL APLASIA

You're already familiar with chloramphenicol, thymoma, and parvovirus as causes of wipe-out of just the red cell precursors.

Many of these patients have a mutation in the ribosomal proteins.
The first discovered was abnormal ribosomal protein S19: Nat. Genet. 21:
169, 1999. There are at least 13 other loci, with heterozygotes (i.e., new mutations)
affected (Blood 109: 1275 & 3152, 2007; Blood 112:
1582, 2008; Blood 117: 2567, 2011) -- the
common theme is a problem with the translational machinery of the ribosome
("anemia lost in translation").

* It often responds to glucocorticoids and often remits with time.
It remains quite mysterious. Marrow transplantation is curative.

THE FANCONI ANEMIAS, now numbering seventeen loci (2015)
are recessive, thankfully rare illnesses. They feature apoptosis of erythrocyte
precursors, as well as a predisposition to cancers (notably the myelodysplastic syndromes
and acute myelogenous leukemia (there's a signature gain of parts of chromosome 1), but
also head-and-neck squamous cancers and some other solid tumors). Often, there's total marrow failure in the end.
Patients tend to be short and have other malformations, especially involving the thumbs.
The products of most (Blood 120: 86, 2012)
of these loci form an important protein complex ("the core complex")
found in both cytoplasm
and nucleus, and that is involved in repair of DNA crosslinks
and the destruction of
damaged cells.
Update J. Clin. Inv.122: 3799, 2012.

The screening test for Fanconi's uses
DNA-crosslinkers like mitomycin C which cause unusually extensive damage
to these cells.

Not surprisingly,
mutations of the Fanconi loci are popping up in sporadic human cancers as well
(Arch. Otol. 132: 958, 2006). Your lecturer predicts that mutations here will be markers
for responses to particular chemotherapeutic agents.

In the chronic hemolytic disorders (notoriously sickle-cell disease, less often spherocytosis or
hemoglobin C disease), the production of normoblasts can simply shut down, even when there's
enough folic acid around. Parvovirus 19 is now known to be the usual cause --
it prevents normoblasts from maturing.
This is called APLASTIC CRISIS.

Future pathologists wishing to spot "parvo":
You will see no normoblasts beyond the basophilic stage,
and the basophilic normoblasts have the nuclear chromatin
pushed to the edge by the viral inclusion.

FINISHING UP: Thankfully, hemoglobins with excessively high
oxygen affinity ("Chesapeake" and many others) are uncommon.
As you'd expect, these render the patient polycythemic.

* Red-cell substitutes have been a disappointment. A bovine hemoglobin
preparation delivers the goods but only lasts for a day in the bloodstream; it is now in
widespread use in some nations and helps JW's in the USA.
The older perfluorocarbon emulsions ("Fluosol", others) required patients to breathe 100% oxygen
which was deadly to the lungs. Review Am. J. Clin. Path. 118 S: S-71, 2002.
Update from the Hop: Arch. Path. Lab. Med. 131: 734, 2007. Nothing else lately.

Sooner or later, you will run into the issue of blood for Jehovah's Witnesses.
The group is authoritarian, tightly-controlled,
and forbids blood transfusions for its members.

Ask a spokesperson for the details. "Many Jehovah's Witnesses
feel that accepting a blood transfusion will lead them to eternal
damnation" (Ob. Gyn. 102: 173, 2003).
Here are some references that
will help you in your thinking.

On the one hand...

It is hard not to admire people who give up their lives
for moral principles -- even if the rest of us think they are misguided (even deceived).
This is very clear in the case of a Jehovah's Witness freely refusing
blood and dying as a result. US law is unequivocal in supporting
the rights of adults to do this.
Likewise, Jehovah's Witnesses around the world go to prison rather than
serve in the armed forces.
As a beginning Christian, I belonged to a pacifist denomination, and
although I eventually decided this position was wrong (at least for me),
I retain a special admiration for anybody who takes the hard road
because something else is of ultimate importance.

For some reason that nobody has explained in the refereed medical
literature, Jehovah's Witnesses are free to accept fractions made from
red cells, from white cells, from platelets, or from plasma. However, they may not take
any of the fractions themselves, or whole blood.
They appear quite willing to accept stem cells from other people
(Bone Marrow Transplantation 32: 437, 2003).

The leadership seems to have reversed itself (June 2000) and now permits use of the
cell recycler (which made possible the JW's much-touted "triumphs of bloodless surgery")
and polymerized cow's hemoglobin. Ask first.

Members believe that if a child is transfused, he/she can be
"cut off" from the possibility of obtaining eternal life
(J. Emerg. Med. 14: 251, 1996). In the 1980's, one
spokesman told me that the child would be stigmatized, regarded
as satanic, and that this was something to take into account before
transfusing a child against the parents' wishes.
More recently I have been reassured that this will not
happen.

There is a saying among blood bankers that we are the only
business people in the community who work hard to reduce demand
for our product. I never saw the point to most "routine" transfusions.
So I was not at all surprised when a Portland bloodless surgery
group
found that Jehovah's Witnesses who had total abdominal hysterectomies
without blood transfusions did as well as or better than controls who had
transfusions (Am. J. Ob. Gyn. 180: 1491, 1999; plus, remember
these folks don't smoke or drink). Obviously it would
be stupid (at best) to generalize this to more serious surgery,
or to hematologic disease.

Several sensitive articles have appeared that physicians
may find helpful in understanding those whose values differ
(a good one: Am. J. Psych. 156: 304, 1999).

Be sure you do not confuse the JW position against blood
transfusion with the beliefs of other sects against all medical
interventions.

Despite the fact that members insist they are "neutral"
and have no loyalty to any secular government, they do point out
that their legal battles have enlarged the freedoms of their neighbors
(i.e., the government can't make your kids say the pledge of allegiance,
and you can also keep your kids out of sports and the
other extracurricular activities that are so important to most teenagers
even if your kids very much want to participate.)
However, in the landmark, unanimous Supreme Court decision "Chaplinsky vs. New Hampshire",
the court ruled that a Jehovah's Witness cannot scream hateful things
about other people's religions on a streetcorner
(the "fighting words" doctrine).

Unlike other militants (the anti-biotechnology people,
the anti-animal-research people, the anti-stem-cell people),
the Jehovah's Witnesses are not trying to force ideology
and a disinformation campagin on
everybody else, or interfere with medical progress.
Especially for this
reason, I urge you to respect them.

On the other hand...

No reasonable person questions that blood transfusions save lives,
and sometimes are necessary to save lives.
Members do die because they refuse transfusions, and not because
of lack of surgical skill.
I cannot address the
spiritual issues. But literature that I've seen from the Jehovah's Witnesses
on the risk-benefit ratio for transfusions in very-sick people
seem to me to be one-sided at best.

A Jehovah's Witness woman is 44x more likely to die in childbirth
than a woman who will accept a blood transfusion (Am. J. Ob. Gyn. 185:
893, 2001 -- as you'd expect, a plan to "optimize hemoglobin using erythropoietin
prior to delivery" in these women was a dismal and expensive failure)

In Italy (and probably elsewhere in Europe), most physicians will not even
undertake the workup of an adult JW with likely leukemia, because of
all the problems that blood refusal will
create. (In the US, this probably shocks us, but think about it.
Problems range from additional public
expense to increased likelihood of a bad outcome to dealing with
militants and snoops to watching somebody actually die of anemia or thrombocytopenia
as a result
of your chemotherapy and being forbidden to save them.)
A team in Milan has actually developed a protocol for JW's with adult
leukemia: Eur. J. Haem. 72: 264, 2004, and has gotten some complete remissions;
they argue that hematologists should reconsider the boycott and I'm inclined to agree.

Jehovah's Witnesses who should have RhoGam
but refuse it (nowadays they are allowed a choice) are asking for death
in utero or a trip to court shortly after birth for their next child.

In Bulgaria, the Jehovah's Witnesses accepted
a government condition,
allowing them to collect money and proselytize
only if they promised not to punish members who received blood
transfusions. This may now be official policy worldwide
(Lancet 356: 1114, 2000).
The denomination used to forbid immunizations and organ
transplantations, but has reversed itself. In the 1930's, the denomination
conducted an inflammatory disinformation campaign against
aluminum cookware. With no basis in fact, the JW's viciously smeared
the medical profession
as evil conspirators
against the health of the public. This is now factual history.
Perhaps the position on
transfusion will change too.
So far as I know, all sects have made ghastly mistakes
at one time or another. Some acknowledge their past
errors.
Others don't.

Since 1961, any adult member who accepts a blood transfusion
knows he or she will be disfellowshipped and shunned (i.e., you are allowed
no contact with anyone who still belongs to the cult.)
For example, the member will not get
to go to his/her children's weddings or his/her parents' funerals.
The marriage will probably break up, the rest of the family will
try to keep the children away
from the disfellowshipped parent, and friendships will end.
When a Jehovah's Witness is in the hospital, the "visitation committee"
comes around to remind doctors not to transfuse their fellow-believer,
and of course to snoop and be sure there's no transfusion.
Blogs (you can find them yourself) talk about grown children
of disfellowshipped members trying to see their dying parent
at the hospital. The "visitation committee" may well be keeping watch outside
the dying parent's room -- and
if the child even speaks a parent who accepted a blood transfusion
thirty years ago, the child, too, will be "disfellowshipped."
WITH PRESSURES LIKE THIS, I THINK REASONABLE PEOPLE CAN ASK WHETHER REFUSING A
NEEDED TRANSFUSION IS REALLY A FREE CHOICE.

When I was doing blood banking as a pathologist, I got tired of the "hospital visitation
committee"
people marching into the lab and saying, "Thus-and-so is a patient in this
hospital and is a Jehovah's Witness, be very sure you don't transfuse him/her."
I found it hard to be polite to these people, and of course got told I was "damned eternally."
With HIPPA, of course, you need to tell these people nothing beyond to get out and stay out.

"The tort of misrepresentation": Legal scholars are now arguing about whether
there exists "THE PRIVATE RIGHT TO SUE WHEN
A RELIGION MISREPRESENTS SECULAR FACTS", i.e., for lying to the faithful about the
scientific facts relating to blood transfusion. A legal case in which a bereaved father sued
the JW's for knowingly lying to his leukemic daughter about the medical facts
has been dragging on for years in Canada. The deceit
in the 2006 edition of "How can blood save your life?" is there for anyone
to see.
"Still, for years claims have been made the blood saves lives."
"One death for every 13,000 bottles of blood transfused", data from 1960.
A barrage of half-truths and outright lies follows, including
the suggestion that the blood you get in an American hospital
may come from a developing nation and not be screened for disease,
or that "we cannot assume that all blood is yet being tested [for AIDS]",
or the shameless, blatant lie that the US blood supply is not screened for HTLV-1.
If the JW's weren't a religion, they'd be in serious trouble
already over the deaths they've caused. See the landmark article,
"Jehovah's Witnesses, Blood Transfusions and the Tort of Misrepresentation",
by K. Louderback-Wood, Journal of Church and State, Vol 47, Number 4, pages 783-822, 2005.
It's a review of the quotations from their
indoctrination tract compared with the actual sources -- the pattern of deliberate, consistent deception
seems obvious to me despite the tract being written in lawyer-ese. If this does come to trial, the author of
"How can blood save your life?" will be torn to shreds on cross-examination
in front of the jury. I am wondering about both civil and even criminal charges
against physicians involved in the sect who fail to tell
others, "Now, that one and that one and that one are all lies."

A portion of the indoctrination tract "Blood Transfusion -- How Safe?" downloaded
by me on November 12, 2009 from the Jehovah's Witness official site and seen to be
copyrighted 2006, reveals
a pattern of deception through the use of material that the authors must realize is way out of date.

A 1960 article, from the era before hepatitis B testing, quotes
a risk of one death in 1000 to 3000 or possibly 5000 transfusions." There is no
more current data cited.

The JW's cite US News and World Report from May 1, 1989, claiming that
"about 5% of those given blood in the United States get hepatitis --
175,000 people a year. About half become
chronic carriers, and at least 1 in 5 develop cirrhosis or cancer of the
liver. It is estimated that 4000 die." What the JW's do not mention
is that this was BEFORE we tested all units for hepatiits C, which is
now vanishingly rare after transfusion.

The JW's quote someone at the American Red Cross from 1989, saying
"We can't just keep adding test after test for each infectious agent
that might be spread." In fact, we have been doing just that whenever possible.
Consider the case of West Nile. And as soon
as transfusion-related prion disease became recognized on the basis of
one case, we began screening all units.

The JW's claim "Even the test for hepatitis B is fallible; many still
contract it from blood." Many? The JW's are being deliberately vague.
Nowadays the risk from a screened unit is about 1 in 150,000.

Initially, we screened for hepatitis C using the antibodies
that patients generate themselves.
The JW's write, "Moreover, will people be satisfied with the announced
test for hepatitis C? The Journal of the American Medical Association
(January 5, 1990) showed that a year can pass before antibodies of the disease
are detectable by the test." What the JW's don't tell their readers is that
NAT testing was added in 1999, detecting the virus itself. Today no one knows
the risk, but it is apparently less than 1 in one million screened units.

The JW's cite the "window period" during which a donor's blood may contain
HIV without an antibody. They cite examples from the past, in which
people were infected in this way. What they fail to tell their readers
is that in 1999, nucleic acid amplification testing was introduced to detect
the virus itself, and the risk is presently estimated at less than 1 in 1,900,000
units transfused.

The JW's write about a virus that "is believed to be the cause of adult T-cell
leukemia / lymphoma and a severe neurological disease." They are referring to HTLV-I.
They claim, "This virus is already in the blood donor population and can be spread in blood."
What they do not tell their readers is that since HTLV-I and HTLV-II were discovered
in the 1980's, all units are now screened for both viruses and the risk of getting
sick is so low that it's not known.

Finally, the JW's use sleight-of-mouth to make readers believe their blood
may not be screened for disease at all.
"We cannot assume that all blood is yet being tested.
For example, it is reported that by the start of 1989, about 80% percent of Brazil's
blood banks were not under government control, nor were they testing for AIDS."
But in the developed world, in 2009? Get real.

Elsewhere in the indoctrination tract ("The Blood That Really Saves Lives"), the JW's
cite a classic study "Effects of Early Transfusion on Gastronintestinal Haemorrhage",
Br. J. Surg. 73: 783-5, 1980. Here is how the JW's represent the article:

The British Journal of Surgery (October 1986) reported that prior to the advent of
transfusions, gastroinestinal hemorrhage had "a mortality rate of only 2.5 per cent." Since
transfusions became customary, "most large studies report a 10-percent mortality."
Why a death rate four times as high? The researchers suggested: "Early blood transfusion
appears to reverse the hypercoagulable response to haemorrhage thereby encouraging
rebleeding."

The researchers were actually examining the old-fashioned, unscientific practice of
early blood transfusions for GI bleeders. Since the figure of 2.5% is astonishingly
low and comes from a paper from 1924, it may reasonably be questioned, and the authors
also note that the 1924 population was a selected group of young, physically-fit individuals
who may have gone straight to surgery.
The underlying causes of the bleeding aren't stated, but we may think that
the 1986 study included many inoperable cirrhotics, who typically bleed to death sooner or later
regardless of what we have to offer.
The JW's are apparently trying to trick the reader into believing
that the 1986 study was a comparison between GI bleeders who were
transfused and those who were not transfused. The researchers actually compared patients who were
transfused when they came in versus patients who were transfused only if their
hemoglobin dropped below 8 g/dL. The authors explain:

Of the 26 patients randomized to receive no blood transfusion within 24
hr of admission, five did require transfusion on their first day for anaemia
worse than 8 g/dl.

No scientific physician will be surprised that patients who were transfused
for no real reason ended up doing worse and requiring more blood in the long
run than patients for whom transfusion was delayed. You're just supplying
more pressure to keep the pumper open.
The authors finish up:

The role of blood transfusion in the treatment of gastrointestinal haemorrhage
has never been questioned seriously although it is accepted that
patients who are transfused more than 4 units of blood fare worse than those
who require less than 4 units.

Go figure -- they must have also been sicker to begin with. The authors conclude from their study,

Therefore, where possible, blood transfusion should be delayed.
If it does need to be given for severe haemorrhage, early surgery
should be considered.

I think a reasonable person would agree that the purpose and findings of the
study should not be presented as part of an overall indictment of blood transfusion.

The JW's have the integrity to admit that their members' refusal
of blood does indeed cost some of them their lives.
They might cite a large study from the Netherlands (BJOG 116: 1103, 2009)
showing figures for women giving birth:

Women who are Jehovah's witnesses are at a six times increased risk for maternal
death, at a 130 times increased risk for maternal death because of major
obstetric haemorrhage and a 3.1 times increased risk for serious
maternal morbidity because of obstetric haemorrhage, compared
to the general Dutch population.

Better surgical techniques today have greatly reduced the need for blood
transfusion during most (not all) major surgeries (Ann. Royal College Surg. 87: 3, 2005).
This is where the JW recently got their host of "facts and figures" to "show" that the
no-transfusion major surgeries that they demand
are actually LESS expensive overall. If this were true, the hospital administrators (driven
by the profit motive) and the resesarch piranhas
would have sat up and taken note. They haven't.
Anesth. Clin. N.A. 23: 327, 2005 didn't look at JW-style "bloodless surgery" at all,
only at heart surgeons' perhaps overusing blood transfusions.
Am. J. Ob. Gyn. 180: 1491, 1999 ("no increased hospital charges")
was simply for routine hysterectomies for JW's.
A celebrated "bloodless surgery" triumph of spinal surgery (Minerva Anesth. 73: 323, 2007)
used autologous donations beforehand.
Anyone who is scientifically
literate will recognize the common fallacies (cherry-picking, failure to control
for other variables, i.e., the sicker people are the ones who get transfused;
a dead patient costs nothing;
surgeons will not operate a JW who is likely to die without a transfusion).
Anyone believing that the "bloodless surgery" that saved the life (barely)
of a JW with a 30 pound sarcoma was cheap or should be the norm (J. Surg. Ed. 64: 212, 2007)
isn't thinking. Will the rest of America keep paying extra for this?

It's my hope that this will be helpful to physicians counselling folks
who have read the indoctrination tract. The public cannot keep itself up-to-date
on all scientific issues. However, most people DO eventually
catch on when they are being lied to,
and they do NOT like it. My livelihood depends on my being known as an
honest man of science. I have risked personal harrassment by placing these notes
on line, simply in the hope that
someone, somewhere will use them to
de-hoax a victim and save ultimately save a life.
One member of the anonymous
group says a physician has a duty, in informed consent, to tell JW's that the booklet is deceptive.
You decide.

Because it seems to me that it is only a matter of time before
the JW leadership pays the price for "the tort of misrepresentation", I do not
intend to discuss this further. Call me unspiritual if you want.

A group within the Jehovah's Witnesses sect that accepts blood
transfusions remains entirely anonymous -- if any member of this
group were to use his/her name in public, he/she would be disfellowshipped
and lose his/her family as a punishment (J. Med. Ethics 26: 375, 2000).
One member was disfellowshipped simply for
writing a supportive e-mail to the group --
his wife turned him in.
Click here
for the physicians' page of the Associated Jehovah's Witnesses for Reform on Blood.
One ethicist suggests that physicians need to tell Jehovah's Witnesses
that the group exists (J. Med. Ethics 26: 299, 2000) -- I agree but doubt
this would have any effect. Much more likely is showing them that they've been
lied to about the secular facts -- in my own experience, people leave
"movements" when, and only when, they discovered they have been
maliciously deceived.

Please remember that for any denomination,
the leadership is not the members.
Where dissent is not tolerated, you cannot know the hearts of
the faithful. I have found individual members to be motivated
by an uncommon concern for my own spiritual well-being, which I appreciate
despite my disagreements. However...
the denominational leadership often finds itself
under sharp public criticism.
In 1987, it expressly instructed members who work in the health-care
setting to breach medical confidentiality. In the cited example,
a member who learned
that another member had an abortion was expected to announce this
to the congregation. Of course
this is a crime in many jurisdictions
(J. Med. Ethics 26: 381, 2000), and as a physician,
simply having people like this around me makes me
extremely uncomfortable.
When one ethicist suggested a don't ask, don't tell approach
for Jehovah's Witnesses needing blood
(J. Med. Ethics 25: 469, 1999), the denomination's lawyers
responded with a piece (J. Med. Ethics 25: 463, 1999)
full of more venom and obvious distortion than I had ever seen
in a journal article.
Letting children know that they are set apart from an evil world
includes requiring them to leave the classroom during other children's
birthday parties. Most are not allowed to participate in
sports or extracurricular activities, i.e., the situations in
which they would probably develop friendships with non-JW's.
There are over 1000 divorce actions in the US each year because one
partner embraces the sect and the other does not, and these tend to be
extremely bitter.
Beginning in 2001, the media gave a lot of attention to
the supposed massive protection of pedophiles and punishments meted out to the
children who bring accusations even if they're probably true. As we've seen before,
this is a politicized subject where it's often hard to get at the truth.
But throughout the crisis, despite the resignation of church leader
William H.
Bowen over
the issue (he called the sect a "pedophile's paradise"), the main JW internet site continued silent.
And right or wrong,
people seem to judge the denomination by its
focus on direct put-you-on-the-spot,
proselytization
and staying uninvolved with our tolerant, pluralistic mainstream society
rather than community service and philanthropy.
The notions of altruism, kindness to strangers, and universal love -- ideas
that are absolutely central
to all the major world-faiths as I know them -- are conspicuously
absent from what I've read of the JW literature. However,
I have known several individual members who
have been among the nicest people I've known,
and during the years when I considered a pacifist commitment,
I came to admire them very much.
One commentator on these notes in 2004 wrote to me that
there cannot possibly be general peace and goodwill among
human beings until "there is only one religion left standing."
There's literature with pictures depicting the supernatural
mass-slaughter of all non-JW's. It's obviously directed toward simple
folks and children.
I don't appreciate this.
The denomination also teaches that family members who accept transfusion
or drop membership should be killed by stoning, and the fact
that they do not do so is merely because national law forbids it.
There are stories on the internet of JW children going to see a
"disfellowshipped" parent during the final illness, only to be warned
by the "visitation committee" (standing outside the patient's room) that if the
child speaks to the parent, the child too will be "disfellowshipped".
This is outside my experience one way or the other -- of course, nowadays
we have the right to bar unwanted snoops.
In France and Italy, most physicians simply
transfuse Jehovah's witnesses while they're asleep in surgery,
without telling them or simply lying
(Eur. J. Anaesth. 8: 297, 1991;
Med. Educ. 36: 479, 2002). I find this unacceptable; others
may disagree, feeling that these people's choice -- in contrast
to the choices your physician must offer you -- is neither honestly-informed
nor free.

For the clinical strategies in managing Jehovah's Witnesses,
see Am. J. Med. 119: 1013, 2006.
The most helpful article on the personal issues that
I've found is J. Med. Eth. 24:
295, 1998. The author urges physicians to help patients make a
genuinely free, informed decision by conferencing with them,
giving accurate information, and asking them why they believe
as they do and what pressures are on them. Whatever decision
the adult patient reaches must be honored.

Let the young sing songs of death. They are stupid. The finest
thing under the sun and the moon is the human soul. I marvel
at the small miracles of kindness that pass between humans.
I marvel at the growth of conscience, at the persistence of
reason in the face of all superstition and despair. I
marvel at human endurance.

-- Anne Rice, "Pandora" ("The
Vampire Chronicles")

BIBLIOGRAPHY / FURTHER READING

I urge anyone interested in learning more about
diseases of red blood cells
to consult these standard textbooks.

In my notes, the most helpful current
journal references are embedded in the text.
Students using these during lecture strongly prefer this.
And because the site is constantly being updated,
numbered endnotes would be unmanageable.
What's available online, and for whom, is always changing.
Most public libraries will be happy to help you get an article
that you need. Good luck on your own searches, and again,
if there is any way in which I can help you, please contact me at
scalpel_blade@yahoo.com.
No texting or chat messages, please. Ordinary e-mails are welcome.
Health and friendship!